rs781745158

Positions:

• chr5-128374657-G-C
• chr5-128374657-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001999.4(FBN2):​c.2066C>G​(p.Ala689Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.95

Genes affected

FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.2066C>G	p.Ala689Gly	missense_variant	15/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.1913C>G	p.Ala638Gly	missense_variant	14/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.2066C>G	p.Ala689Gly	missense_variant	15/65	1	NM_001999.4	ENSP00000262464	P1
FBN2	ENST00000508989.5	c.1967C>G	p.Ala656Gly	missense_variant	14/33	2		ENSP00000425596
FBN2	ENST00000511489.1	n.287C>G		non_coding_transcript_exon_variant	3/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461676 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital contractural arachnodactyly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 05, 2016

In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN2-related disease. This sequence change replaces alanine with glycine at codon 689 of the FBN2 protein (p.Ala689Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;D;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;.;.;T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.50	T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.1	L;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.8	D;.;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.033	D;.;D;D
Sift4G	Benign	0.14	.;.;.;T
Polyphen		0.64	P;.;P;D
Vest4		0.60
MutPred		0.63		Gain of disorder (P = 0.0283);.;Gain of disorder (P = 0.0283);.;
MVP		0.59
MPC		0.67
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.25
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781745158; hg19: chr5-127710350;